CYLD Regulation of Epidermal Growth and Neoplasia

CYLD 对表皮生长和肿瘤的调节

• 批准号: 7477788
• 负责人: Jennifer Yunyan Zhang
• 金额: $ 7.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477788
• 关键词: Abnormal Cell; Adaptor Signaling Protein; Address; Adult; Alleles; Apoptosis; Biochemical; Biology; Birth; Cell Cycle Progression; Cell Proliferation; Cell Surface Receptors; Cells; Chemicals; Cutaneous; Data; Epithelial; Epithelial Neoplasms; Etiology; Gene Silencing; Goals; Growth; Homeostasis; Human; Hyperplasia; In Vitro; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Mus; Mutate; Mutation; Neoplasms; Oncogenes; Oncogenic; Other Genetics; Pathogenesis; Pathway interactions; Patients; Play; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Skin Tissue; Skin graft; Small Interfering RNA; Squamous cell carcinoma; Surface; Testing; Transcription Factor AP-1; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; Tumor Tissue; UV induced; Ubiquitination; appendage; base; cell growth; environmental change; genetic linkage; human tissue; in vivo; insight; keratinocyte; loss of function mutation; mutant; penis foreskin; prevent; promoter; response; retroviral-mediated; skin disorder; stress-activated protein kinase 1; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Recent studies have established a genetic linkage of cyld to both familial and sporadic neoplasms that mostly arise from the epidermal cells of skin appendages, as distinct from surface epidermal cells. CYLD acts as a deubiquitinase that inhibits self-ubiquitination of TRAF2/TRAF6 proteins, the key adaptor molecules mediating signal transduction from cell surface receptors, and thereby inhibit downstream signaling pathways, including NF-?B and JNK signaling cascades. A previously predicted role for the canonical NF-?B pathway in the etiology of skin neoplasms was recently challenged by findings revealing unaltered NF-KB RelA function in the TPA-induced hyperproliferation of cyld-/- mice epidermal cells. In addition, we have recently demonstrated that NF-?B is crucial in epidermal growth control and its blockade contributes to squamous cell carcinoma (SCC) in a JNK/AP1 function dependent manner. These finding lead us to hypothesize that CYLD inhibition acts through JNK cascade to promote neoplasia. The first goal of this study is to define the mechanisms of CYLD regulation of epidermal cell growth and to explore whether the JNK signaling cascade play a central role in CYLD effects on epidermal homeostasis. To do this, we will isolate multiple types of primary human epidermal cells from surgically disposed foreskin or adult skin and study their growth response to genetically modified CYLD function, as well as JNK signaling. The second goal is to study CYLD-driven neoplasia in vivo by generating both mice and human transgenic skin tissue. We will investigate whether inhibiting or augmenting NF-?B, JNK or Ras-MAPK signaling cascades will prevent or potentiate CYLD induced neoplasia. By the end of this proposal, we hope to have determined the mechanism of CYLD regulation of epidermal homeostasis and cutaneous epithelial neoplasms. This effort is based on the premise that characterizing the molecular mechanisms in CYLDmediated cell growth and neoplasia in skin tissue will both provide new insights into basic epithelial biology as well as characterize therapeutic targets for human skin diseases.

描述（由申请人提供）： 最近的研究已经建立了CYLD与家族性和零星肿瘤的遗传联系，主要是由皮肤附着的表皮细胞引起的，与表面表皮细胞不同。 CYLD充当抑制TRAF2/TRAF6蛋白的自我泛素化的去泛素酶，这是关键衔接子分子，从细胞表面受体中介导信号转导信号转导，从而抑制下游信号通路，包括NF-？B？b和JNK信号级联。最近发现，在TPA诱导的CYLD-/ - 小鼠表皮细胞中揭示了未更改的NF-KB RELA功能，揭示了未改变的NF-KB RELA功能的发现，该法典NF-途径在皮肤肿瘤的病因中的先前预测作用。此外，我们最近证明，NF-？B在表皮生长控制中至关重要，其阻断以JNK/AP1函数依赖于鳞状细胞癌（SCC）有助于鳞状细胞癌（SCC）。这些发现使我们假设CYLD抑制通过JNK级联反应来促进肿瘤。这项研究的第一个目标是定义表皮细胞生长的CYLD调节机制，并探索JNK信号级联是否在CYLD对表皮稳态的影响中起核心作用。为此，我们将分离多种类型的原代人表皮细胞与外科手术外科或成年皮肤，研究其对转基因CYLD功能以及JNK信号传导的生长反应。第二个目标是通过产生小鼠和人类转基因皮肤组织来研究体内CYLD驱动的肿瘤。我们将研究抑制或增强NF-？b，JNK或RAS-MAPK信号传导级联反应会预防或增强CYLD诱导的肿瘤。在该提案的结尾，我们希望确定表皮稳态和皮肤上皮肿瘤的CYLD调节机制。这项工作是基于以下前提：表征在皮肤组织中细菌细胞生长和肿瘤中的分子机制都将为基本上皮生物学提供新的见解，并为人类皮肤疾病的治疗靶标提供了新的见解。